Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. The development of chemoprotectants is the central goal of this Phase I proposal. In preliminary studies, Reaction Biology Corporation has completed three separate high throughput screening (HTS) campaigns for small molecular regulators of cellular survival. Three specific aims are proposed: (1) validation of hits in cell culture;(2) hit-to-lead chemistry program to advance the most promising chemistries;and (3) testing of compounds in cell lines for radiotoxicity. Such compounds will be used topically or by direct injection and do not require traditional oral activity and therefore may deviate to some degree from classic Lipinsky and ADMET constraints. Since chemotherapy and radiotherapeutic approaches are dose-limited due to off-target toxicity, the use of cell survival promoting agents during cancer treatments may offer several benefits to patients. PUBLIC HEALTH RELEVANCE: Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. Even though apoptosis is considered the central theme in oral mucositis, little work with caspase inhibitors has been conducted to date. Reaction Biology Corp. has developed a few novel, potent and selective caspase inhibitors and would like to evaluate their cell death protection activities in radiation induced apoptosis assays. The potent chemoprotectants will be further optimized and evaluated in mice models in next phase study.